Automatic Adaptation of A-V Delay and HR for Heart Failure using Beat to Beat Measures

ABSTRACT

Methods and systems to modulate timing intervals for pacing therapy are described. For each cardiac cycle, one or both of an atrioventricular (A-V) timing interval and an atrial (A-A) timing interval are modulated to oppose beat-to-beat ventricular (V-V) timing variability. Pacing therapy is delivered using the modulated timing intervals.

RELATED PATENT DOCUMENTS

This application is a divisional of U.S. patent application Ser. No.11/799,794, filed on May 3, 2007, to which priority is claimed under 35U.S.C. §120, and which is incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates generally to cardiac pacing therapy, andmore specifically, to automatic adjustment of pacing intervals.

BACKGROUND

When functioning normally, the heart produces rhythmic contractions andis capable of pumping blood throughout the body. The heart hasspecialized conduction pathways in both the atria and the ventriclesthat enable the rapid conduction of excitation impulses (i.e.depolarizations) from the SA node throughout the myocardium. Thesespecialized conduction pathways conduct the depolarizations from the SAnode to the atrial myocardium, to the atrio-ventricular node, and to theventricular myocardium to produce a coordinated contraction of bothatria and both ventricles.

The conduction pathways synchronize the contractions of the musclefibers of each chamber as well as the contraction of each atrium orventricle with the opposite atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Patients who exhibit pathology of these conduction pathwayscan suffer compromised cardiac output.

Cardiac rhythm management devices have been developed that providepacing stimulation to one or more heart chambers in an attempt toimprove the rhythm and coordination of atrial and/or ventricularcontractions. Cardiac rhythm management devices typically includecircuitry to sense signals from the heart and a pulse generator forproviding electrical stimulation to the heart. Leads extending into thepatient's heart chamber and/or into veins of the heart are coupled toelectrodes that sense the heart's electrical signals and for deliveringstimulation to the heart in accordance with various therapies fortreating cardiac arrhythmias.

Pacemakers are cardiac rhythm management devices that deliver a seriesof low energy pace pulses timed to assist the heart in producing acontractile rhythm that maintains cardiac pumping efficiency. Pacepulses may be intermittent or continuous, depending on the needs of thepatient. There exist a number of categories of pacemaker devices, withvarious modes for sensing and pacing one or more heart chambers.

Pacing therapy has been used in the treatment of heart failure (HF). HFcauses diminished pumping power of the heart, resulting in the inabilityto deliver enough blood to meet the demands of peripheral tissues. HFmay cause weakness, loss of breath, and build up of fluids in the lungsand other body tissues. HF may affect the left heart, right heart orboth sides of the heart. For example, HF may occur when deterioration ofthe muscles of the heart produce an enlargement of the heart and/orreduced contractility. The reduced contractility decreases the cardiacoutput of blood and may result in an increased heart rate. In somecases, HF is caused by unsynchronized contractions of the left and rightheart chambers, denoted atrial or ventricular dysynchrony. Particularlywhen the left or right ventricles are affected, the unsynchronizedcontractions can significantly decrease the pumping efficiency of theheart.

Pacing therapy to promote synchronization of heart chamber contractionsto improve cardiac function is generally referred to as cardiacresynchronization therapy (CRT). Some cardiac pacemakers are capable ofdelivering CRT by pacing multiple heart chambers. Pacing pulses aredelivered to the heart chambers in a sequence that causes the heartchambers to contract in synchrony, increasing the pumping power of theheart and delivering more blood to the peripheral tissues of the body.In the case of dysynchrony of right and left ventricular contractions, abiventricular pacing therapy may pace one or both ventricles. Bi-atrialpacing or pacing of all four heart chambers may alternatively be used.

SUMMARY

Embodiments are directed to systems and methods for automatic adjustmentof pacing intervals. One embodiment is directed to a method fordelivering pacing therapy to a heart. For each cardiac cycle, one orboth of an atrioventricular (A-V) timing interval and an atrial (A-A)timing interval are modulated to oppose beat-to-beat ventricular (V-V)timing variability. Pacing therapy is delivered using the modulatedtiming intervals.

In some implementations, a sensor indicated pacing rate may bedetermined based on the patient's physiological status and the timingintervals of the indicated pacing rate may be modulated to opposebeat-to-beat ventricular (V-V) timing variability. Physiological statusis determined, for example, by sensing metabolic need, autonomic toneand/or hemodynamic status.

In addition to modulating the A-V and A-A intervals, one or more of aninterventricular delay interval, an intraventricular delay interval, aninteratrial delay interval, or an intraatrial delay interval may also bemodulated to improve cardiac function.

Modulation of the timing intervals may be effected to produce optimalstroke volume for each beat. As the base pacing rate is varied toproduce physiologic respiratory sinus arrhythmia, the timing intervalsmay also be modulated based on respiration. An amount or degree of themodulation may be a function of exertion level or heart rate.Independent modulation of the timing intervals may be based on one ormore parameters that affect heart function. The parameters may include,for example, one or more of stroke volume, blood pressure, blood flow,cardiac contractility, baroreflex, chemoreflex and/or other parameters.

One implementation involves sensing a physiological parameter of a rightheart chamber during a cardiac cycle. The timing intervals areindependently modulated for a next cardiac cycle based on the sensedright heart chamber parameter.

The timing intervals can be initially determined using an algorithmdesigned to optimize the pacing intervals for a particular type ofdisorder experienced by the patient, such as heart failure. For example,modulating the timing intervals may involve modulating anatrioventricular interval and/or interventricular delay interval and/orother timing intervals to provide cardiac resynchronization therapy.

Another embodiment is directed to a cardiac rhythm management device.The device includes a sensor system configured to sense one or morephysiological parameters. For each cardiac cycle, a therapy controlprocessor independently modulates one or more of atrial (A-A) timinginterval and an atrioventricular (A-V) timing interval to opposeventricular (V-V) timing variability based on the sensed physiologicalparameters. A therapy delivery system delivers pacing to the heart usingthe independently modulated timing intervals. The sensor system mayinclude, for example, a respiration sensor and the therapy controlprocessor may control deliver of pacing based on respiration cycle phaseto mimic natural respiratory sinus arrhythmia. Modulation of the pacingtiming intervals may also occur based on respiration cycle phase.

According to one aspect, the therapy control processor is configured tomodulate the A-A and A-V timing intervals to cancel fluctuations in theV-V intervals within one beat at elevated heart rates. In addition, thetherapy control processor may be further configured to modulate one ormore of an interventricular timing interval, an intraventricular timinginterval, an interatrial timing interval, and an intraatrial timinginterval.

In one implementation, the sensor system is configured to sense aphysiological parameter of a right heart chamber during a cardiac cycle.The therapy control processor independently modulates the timingintervals of the indicated pacing rate for a next cardiac cycle based onthe sensed right heart chamber parameter. Rate dependent modulation ofthe pacing timing intervals may be used to produce optimal stroke volumefor each cardiac beat at elevated heart rates.

In certain configurations, the therapy control processor is configuredto control delivery of non-excitory electrical stimulation to altermyocardial contractility. The therapy delivery system is configured todeliver the non-excitory electrical stimulation under control of thetherapy control processor.

The above summary is not intended to describe each embodiment or everyimplementation of the present disclosure. Advantages and attainments,together with a more complete understanding of the embodiments, willbecome apparent and appreciated by referring to the following detaileddescription and claims taken in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates graphs of the sensor indicated rate as a function ofpatient activity;

FIG. 1B is a graph comparing respiration, blood pressure, and heart ratein a healthy individual;

FIG. 2A is a flow diagram illustrating a method for modulating timingintervals in accordance with some embodiments;

FIG. 2B is a flow diagram that illustrates a method for pacing intervalmodulation that includes variation based on RSA in accordance with someembodiments;

FIG. 2C is a flow diagram illustrates a method for beat-to-beatmodulation of base timing intervals in accordance with variousembodiments;

FIG. 3A is a block diagram of pacing interval modulation circuitryimplementable in a cardiac rhythm management (CRM) device that may beused to determine rate dependent modulation of pacing timing intervalsin accordance with some embodiments;

FIG. 3B is a block diagram of pacing interval modulation circuitry inaccordance with some embodiments;

FIG. 4 illustrates representative graphs of pacing interval modulationcoefficients in accordance with some embodiments;

FIG. 5 is a block diagram of circuitry that may be used for implementinga pacing timing interval modulation in accordance with some embodiments;and

FIG. 6 illustrates a patient-implantable device that may be used inconjunction with a pacing timing interval modulation in accordance withvarious embodiments.

While the disclosed embodiments are amenable to various modificationsand alternative forms, specifics thereof have been shown by way ofexample in the drawings and will be described in detail below. It is tobe understood, however, that the intention is not to limit theparticular embodiments described. On the contrary, the intention is tocover all modifications, equivalents, and alternatives of theembodiments described herein.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

In the following description, references are made to the accompanyingdrawings, which form a part hereof, and which illustrate variousembodiments. It is to be understood that other embodiments may beutilized, and structural and functional changes may be made withoutdeparting from the scope of the disclosure.

Systems, devices or methods may include one or more of the features,structures, methods, or combinations thereof described hereinbelow. Forexample, a device or system may be implemented to include one or more ofthe advantageous features and/or processes described below. It isintended that such device or system need not include all of the featuresdescribed herein, but may be implemented to include selected featuresthat provide for useful structures and/or functionality. Such a deviceor system may be implemented to provide a variety of therapeutic ordiagnostic functions.

Recent studies show that during exercise the intrinsic variability ofthe P-P and R-R intervals decreases, with the decrease in thevariability of the R-R being most pronounced, especially at higher heartrates of about 140-160 bpm. Conversely, variability of the P-R intervaland the change in P-R interval variability increases during exercise.The conclusion drawn from these studies is that at elevated heart ratesthe AV nodal mechanism functions to produce P-R intervals that cancelfluctuations in the P-P intervals within one beat and to decrease thevariability of R-R intervals. (See e.g., “Variability of VentricularExcitation Interval does not Reflect Fluctuation in Atrial ExcitationInterval during Exercise in Humans: AV Nodal Function as Stabilizer,” J.Physiol. Sci. Vol. 56, No. 1, February 2006, pp. 67-77).

As exertion increases from a resting level, stroke volume typicallyincreases and then gradually plateaus. Stroke volume is increasedthrough a number of mechanisms, including increased ventricular preload,decreased ventricular afterload, and increased myocardial contractility.At high levels of exertion, stroke volume remains relatively constantand additional cardiac output is achieved through increased heart rate.

The intrinsic variability of the P-R intervals operates to stabilizebeat to beat stroke volume. For example, if stroke volume decreases as aresult of decreased preload, the AV node operates to elongate the P-Rinterval and shorten the P-P interval whereas if stroke volume increasesdue to increased preload, the P-R interval is shortened and the P-Pinterval is elongated. This effect is especially pronounced duringventilation cycles.

Embodiments are directed to systems and methods to produce beat to beatmodulation of atrial, ventricular, and/or atrioventricular pacing timingintervals to produce physiologic pacing that provides optimal strokevolume. The approaches described herein provide for modulation of one ormore pacing timing intervals for each cardiac cycle, where theatrioventricular (AV) timing interval and/or atrial (A-A) timinginterval are modulated to oppose ventricular (V-V) timing variability.The approaches involve adjusting the timing intervals between one ormore of a sensed or paced atrial beat of a cardiac cycle and a pacedatrial beat for the next cardiac cycle, a sensed or paced ventricularbeat of a cardiac cycle and a paced ventricular beat of the next cardiaccycle, a sensed or paced atrial beat of a cardiac cycle and a pacedventricular beat of the cardiac cycle, an interventricular intervalbetween two ventricular beats of a cardiac cycle, and an interatrialinterval between two atrial beats of a cardiac cycle.

In embodiments described herein, a cardiac rhythm management device,such as an implantable pacemaker or pacemaker/defibrillator, providesrate dependent modulation of pacing timing intervals beat by beat toachieve optimal stroke volume and decreased variability betweenventricular beats to mimic the observed physiologic response discussedabove. Beat to beat modulation of the pacing timing intervals may beperformed automatically by the device based on measures of one or morephysiological parameters, including parameters such as, stroke volume,cardiac output, total peripheral resistance, blood pressure, baroreflex,chemoreflex, cardiac contractility, and/or other measured parameters.

Modulation of the pacing timing intervals in accordance with theembodiments described herein may be superimposed on a pacing rateindicated by rate adaptive pacing and/or to achieve respiration sinusarrhythmia (RSA) or heart rate variability (HRV). Rate adaptive pacinghas previously been accomplished by adjusting the pacing rate inresponse to changes in the sensed physical activity. The pacing ratecalculated for the level of sensed physical activity is typicallyreferred to as the sensor indicated rate or SIR. FIG. 1A illustratesgraphs of the sensor indicated rate as a function of patient activity.In this example, pacing gains of 1-5 may be selected by the user to varythe slope of the SIR graphs. The sensor used to determine the sensorindicated rate typically may be an accelerometer (or other motionsensor) or a minute ventilation (MV) sensor.

Additionally, or alternatively, the pacing rate may be varied to mimicnatural variability of the heart rate (HRV). Under healthy conditions,heart rate and blood pressure vary with respiration. The heart ratevaries in response to autonomic as well as other regulatory inputs tothe sinoatrial node (SA). FIG. 1B is a graph comparing a respirationsignal 102, blood pressure signal 104, and electrocardiogram (ECG) 106in a healthy individual. PR and RR intervals shorten during ventilationand this modulation of heart rate with respiration is known asrespiratory sinus arrhythmia (RSA). The rate variations of RSA have beenfound to be important to survival. Individuals without RSA have higherrates of overall mortality when compared to those with RSA.

Embodiments involve pacing at a rate sufficient to meet the metabolicdemand for the patient's activity level and also introducing ratedependent variability in the pacing timing intervals which serves tostabilize stroke volume beat to beat at elevated heart rates. FIG. 2A isa flow diagram illustrating a method for modulating pacing timingintervals in accordance with embodiments. A SIR for rate adaptive pacingis determined 210 based on the patient's physiologic state. For example,determining the physiological state may involve determining thepatient's metabolic demand based on hemodynamics or respiration over oneor more previous beats. The degree of modulation of the pacing intervalsmay also be a function of metabolic demand with modulation increasingwith exertion and/or heart rate. In some embodiments, metabolic demandis determined through the use of a patient activity sensor, such as anaccelerometer and/or minute ventilation (MV) sensor which is configuredto detect the level of patient activity. The SIR is determined based onthe output of the patient activity sensor.

The pacing timing intervals of the sensor indicated pacing rate aremodulated beat by beat 220 for each cardiac cycle to maintain an optimalstroke volume. Stroke volume is limited by the amount of blood enteringthe ventricle from the atrium between ventricular contractions and maybe increased through various mechanisms including increased ventricularpreload and decreased afterload. The pacing timing intervals may bemodulated to achieve a stroke volume for each cardiac cycle thatprovides optimal cardiac output. An approach involves introducing ratedependent variability into the A-A intervals and the A-V intervals sothat variations of the A-A intervals are compensated for by variationsin the A-V intervals to maintain V-V intervals relatively constant athigher heart rates. Pacing therapy is delivered 230 using the sensorindicated pacing rate and the modulated timing intervals.

In certain embodiments, the approaches may involve varying the SIRand/or modulating the pacing timing intervals with respiration cyclephase to achieve a heart rate that mimics natural RSA. Modulation of thepacing timing intervals to produce the optimal stroke volume beat bybeat is superimposed on the SIR with variations for RSA and may alsotake into account respiratory cycle phase. The flow diagram of FIG. 2Billustrates a method for pacing interval modulation that includesvariation based on RSA. A sensor indicated rate is determined 240 basedon patient activity. The sensor indicated pacing rate is varied 250based on respiration cycle phase to mimic respiratory sinus arrhythmia.Pacing intervals of SIR varied to mimic RSA are varied 260 to provideoptimal beat to beat stroke volume. Therapy is delivered 270 using theindicated pacing rate varied for RSA and the modulated pacing timingintervals.

Various techniques have been used to determine pacing timing intervalsthat increase cardiac pumping efficiency for patients suffering fromvarious disorders that prevent the heart from operating normally. Forexample, one such disorder involves degeneration of the LV conductionsystem, blocking propagation of electrical signals through thespecialized conduction pathways of the heart and causing contraction ofthe LV to occur in stages rather than synchronously. Another disorder ofthe heart occurs when blood in the LV flows backward to the LA resultingin reduced stroke volume and cardiac output. Both of these disorders maybe found separately or in combination in patients exhibiting congestiveheart failure (CHF). Patients suffering from these disorders benefitfrom pacing that improves contractility and/or stroke volume.Embodiments may modulate pacing timing intervals for A-V,interventricular delay (IVD) and/or interatrial delay (IAD) to treat CHFand related disorders. Timing intervals between paces delivered tomultiple electrodes disposed within a single cardiac chamber, denotedintraventricular timing intervals or intraatrial timing intervals, mayalternatively or additionally be modulated. Initial pacing timingintervals for A-V, IVD, IAD, and/or intrachamber timing intervals may beinitially determined using various techniques such as those described inthe following commonly owned U.S. Pat. Nos. 6,144,880, 7,181,285,5,466,245, 5,800,471, 5,334,222, and 6,371,922 which are incorporatedherein by reference. Following determination of initial values for oneor more of these timing intervals, modulation of the timing intervalsaround the initial values may be applied using the approaches. Forexample, an initial AV interval delay determined as optimal from one ofthe techniques described in the above referenced patents may bemodulated beat by beat to achieve optimal stroke volume.

The flow diagram of FIG. 2C illustrates a method for beat to beatmodulation of pacing intervals in accordance with embodiments. A sensorindicated rate is determined 275 based on patient activity. One or morebase pacing timing intervals are determined 280. For example, pacingtiming intervals the AV interval and/or interventricular delay (IVD) maybe determined which are indicated to provide therapy for the patient'sparticular dysfunction. These pacing timing intervals may be programmedinto the device by a physician via a device programmer or may bedetermined by the device. The base pacing timing intervals may beupdated through periodic testing to track changes in the patient'scondition. Once the base pacing timing intervals are determined, thesetiming intervals are modulated 285 to mimic the natural intervalmodulation that occurs as heart rate increases. In some embodiments,modulation to mimic the effects of RSA may also be performed. Therapy isdelivered 290 using the indicated pacing rate and the modulated pacingtiming intervals.

Modulation of the pacing timing intervals may be accomplished usinginputs from various sensors to provide feedback control. For example,measurements of stroke volume, cardiac output, total peripheralresistance, pulmonary artery (PA) pressure, hemodynamics, blood flow,blood pressure (e.g., RV, LV, or arterial blood pressure), autonomictone, baroreflex, chemoreflex, cardiac contractility measurements,and/or other physiological parameters may be used individually ortogether to control the pacing timing intervals of the next beat.

In one embodiment, an algorithm is implemented to generate intervalsthat help to promote or maintain autonomic tone. Autonomic tone canbecome unbalanced during heart disease with more sympathetic tone vs.parasympathetic tone. The algorithm to adjust pacing timing intervalsbased on autonomic tine may be accomplished by changing intervals untilautonomic tone is improved and more balanced.

Baroreflex responds directly to changes in hemodynamics and may be usedto modulate the pacing timing intervals to improve hemodynamics.Chemoreflex may respond to biomarkers such as B-type natriuretic peptide(BNP), atrial natriuretic peptide (ANP), matrix metalloproteinase (MMP),and/or inflammatory markers. Changes in these parameters may signalimproving or worsening health status and may indicate changes ininterval timing would be beneficial.

The parameters may be measured or derived from sensor signals producedby transthoracic impedance sensors, optical sensors, accelerometers,heart sound sensors, PA pressure sensors, RV, LV or arterial pressuresensors, posture sensors, and/or other sensor types. In someimplementations, modulation of the timing intervals for a cardiac cycleis based on one or more parameter values, e.g., stroke volume, cardiacoutput, pressure and/or flow, measured just prior to the cardiac cycle.In other implementations, modulation of the timing intervals is based ona history of parameter measurements, e.g., chemoreflex and/or autonomictone, taken over a relatively longer period of time prior to the cardiaccycle. Approaches for measuring stroke volume and cardiac output,aspects of which may be utilized in conjunction embodiments disclosedherein, are described in commonly owned U.S. Pat. Nos. 4,674,518,4,686,987, and 5,417,717 which are incorporated herein by reference.

Parameter measurements made during a cardiac beat may be used to controlthe pacing timing intervals of the next beat. For example, a right-sidedsensed parameter is particularly useful for controlling pacing timingintervals for the next beat because the right ventricle is one beatahead of the left ventricle during increases in venous blood return(preload). Thus, a right-sided sensed parameter, such as pulmonaryartery (PA) pressure, may be used to provide data to control the timingintervals for the next paced beat.

FIG. 3A is a block diagram of pacing interval modulation circuitry 300of a cardiac rhythm management (CRM) device that may be used todetermine rate dependent modulation of pacing timing intervals inaccordance with embodiments. The circuitry includes a sensing systemhaving sensors 310 configured to sense physiologic parameters that areused to determine base pacing rate, base pacing timing intervals, and tocontrol modulation of the pacing timing intervals. For example, in someimplementations, an accelerometer may be used to provide a signalindicating patient activity level that is used by the pacing ratecircuitry 320 to determine the SIR. A transthoracic impedance sensor maybe used to generate a respiration signal from which respiration cyclephase may be determined. The pacing intervals may be modulated by theprocessor 340 based on the respiration cycle phase to produce pacingthat mimics respiratory sinus arrhythmia.

Values of one or more of the pacing timing intervals, such as the baseAV and/or IVD intervals, may be programmed into the CRM device and/ormay be determined by the pacing interval circuitry 330 using the sensedparameters. Various techniques have been developed to determine pacingintervals to provide effective therapy for patients based on theirparticular pathology. For example, U.S. Pat. No. 7,181,285 describesprocesses for determining an A-V interval based on measured values ofthe intrinsic P-R intervals and determining an IVD interval based on themeasured interval between right and left ventricular events. U.S. Pat.No. 5,334,222 describes a process for determining a A-V interval basedon measures of cardiac function, including stroke volume and cardiacoutput which are assessed using measured intracardiac impedancevariations due to the influx and outflow of blood from one of theventricular chambers. U.S. Pat. No. 5,700,417 describes determining anA-V interval based on mechanical AV delay measured using heart soundsdetected by an accelerometer. U.S. Pat. No. 6,371,922 describesdetermination of the A-V pacing interval based on baroreflex sensitivitymeasured using sensors for monitoring atrial and/or ventricular cyclelength from an electrogram and pulse pressure. U.S. Pat. No. 6,371,922describes determining cycle length from an electrogram signal anddetermining pulse pressure from Doppler echo, radial tonometry,plethsmography, or other techniques.

The interval modulation processor 340 receives the SIR (which mayinclude RSA variation) calculated by the pacing rate circuitry 320. Theinterval modulation processor 340 also receives the base pacing timingintervals determined by the pacing interval circuitry 330. The SIR andbase pacing timing intervals are modulated by the processor 340 toachieve modulation that provides optimal stroke volume for each cardiaccycle. Modulation of the SIR and the indicated pacing timing intervalsis accomplished using one or more of the parameters sensed by the sensorsystem 310. The interval modulation processor 340 uses the parameters tomodulate the timing intervals beat by beat.

In general, the modulated pacing timing intervals for cardiac cycle imay be calculated using Equations [1-3].

AA _(i)=CycleLength_(i) +K ₁·SP_(1i) +K ₂·SP_(2i) + . . . +K_(M)·SP_(Mi)   [1]

VV _(i)=CycleLength_(i) +L ₁·SP_(1i) +L ₂·SP_(2i) + . . . +L_(M)·SP_(Mi)   [2]

ΔAV _(i) =VV _(i) −AA _(i)   [3]

where AA_(i) is the atrial pacing interval between atrial events ofcardiac cycle i-1 and cardiac cycle i; VV_(i) is the ventricular pacinginterval between ventricular events of cardiac cycle i-1 and cardiaccycle i, and ΔAV_(i) is the change in the AV interval of cardiac cyclei-1 and cardiac cycle i. CycleLength_(i) is the cycle length indicatedby the SIR. Sensed parameters SP_(1i), SP_(2i), . . . SP_(Mi) are sensedparameters used to modulate the pacing timing intervals of cardiac cyclei. Modulation coefficients K₁, K₂, . . . K_(M) and L₁, L₂, . . . L_(M)are functions of the SIR. The modulation coefficients of Equations [1-3]can be determined using patient population data or can be individualizedfor a patient. The results produced by Equations [1-3] above can beimproved by increasing the amount and quality of patient population dataand/or individual data used to develop the coefficients.

The coefficients are related to the degree of modulation of the timingintervals and the relative weight given to various parameters indetermining the modulation. As previously discussed, these coefficientsmay be individualized for a particular patient. For example, the devicemay change the degree of timing interval modulation or the weighting fora particular parameter over a period of time while monitoring patientresponses, including, but not limited to activity response, autonomictone, hemodynamic response, chemoreflex response, and/or baroreflexresponse. Using this information, selection of an appropriate degree ofmodulation, the parameters used to control the modulation, and/or theweight given to each parameter for the individual patient may bedetermined.

FIGS. 3B and 4 provide an example of the operation of the pacinginterval modulation circuitry in accordance with an embodiment. In thisembodiment, an accelerometer 312 is used to sense patient activity and atransthoracic impedance sensor 313 senses patient respiration. Thepatient activity signal from the accelerometer 312 is used by the pacinginterval circuitry 321 to determine a SIR. The pacing interval circuitryoutputs cycle length for cardiac cycle i, denoted CycleLength_(i), basedon the SIR. CycleLength_(i) may also be varied for respiration cyclephase, ·φRC_(i), based on the respiration signal produced by theimpedance sensor 313. An AV pacing interval (preAV_(i)) is initiallydetermined by the pacing interval circuitry 331. In this embodiment, thepreAV_(i) pacing timing interval is calculated based on intrinsic P-Rintervals measured from the cardiac electrical signals detected by acardiac electrogram circuitry 311. The preAV_(i) may be calculated toimprove the patient's hemodynamic response, such as an optimized AVdelay for CRT pacing.

The CycleLength_(i), of the SIR and the preAV_(i) pacing timing intervalare input to the interval modulation processor 341. Respiration cyclephase for cardiac cycle i, denoted ·φRC_(i), is determined from therespiration signal generated by the transthoracic impedance sensor 313.The interval modulation processor 341 varies the modulation intervals ofthe SIR based on respiration cycle phase. Ventilation can changeintrathoracic pressures affecting blood return and preload on the heart,causing changes in stroke volume. The pacing timing intervals may bemodulated to compensate for these natural fluctuations in stroke volume.For example, the pacing interval modulation processor may modulate thetiming intervals to deliver an appropriate A-V interval and HRV.

Additionally, the interval modulation processor 341 can modulate thepacing timing intervals of the SIR using the signal derived from asensor 314 that indicates changes in systolic blood pressure (SBP). Forexample sensor 314 may comprise a pressure sensor that provides dP/dt ormay comprise an accelerometer configured to sense heart sounds.

The level of the SIR may also be used to determine the level ofmodulation of the pacing intervals to achieve the rate based modulationdescribed herein. For example, at rest, the pacing interval modulationmay affect both the A-A and V-V intervals nearly equally. With increasedexercise, A-A modulation decreases but remains present to some degree.As the heart rate increases, modulation in the A-A interval is nearlycancelled by modulation of the A-V interval to keep the V-V intervalsubstantially constant.

For example, for the embodiment illustrated by FIG. 3B, the modulatedpacing timing intervals for cardiac cycle i may be calculated usingEquations [4-6].

AA _(i)=CycleLength_(i) +a·φRC _(i) +b·ΔSBP _(i)   [4]

VV _(i)=CycleLength_(i) +a φRC _(i) +c·ΔSBP _(i)   [5]

ΔAV _(i) =VV _(i) −AA _(i)   [6]

Modulation coefficients a, b, and c are a function of the SIR.Representative graphs of modulation coefficients a, b, and c areillustrated in FIG. 4. These graphs may be developed based on patientpopulation data as previously discussed.

FIG. 5 is a block diagram of a CRM device 500 including a therapycontroller 510 incorporating pacing interval modulation circuitry 501 inaccordance with embodiments. Cardiac electrode 545 may be positioned ordisposed at multiple locations within a heart chamber or vasculature.

One or more sensors 530 are configured to sense physiological parametersused to determine a SIR, detect respiration cycle phase, determine aninitial AV interval and provide rate based modulation of the pacingtiming intervals as discussed above. Useful sensors 530 include a sensoror sensors that detect heart sounds (e.g., microphone, accelerometer), apressure sensor (e.g., left arterial pressure sensor such as a pulmonaryartery pressure sensor, right ventricular pressure sensor), and acardiac stroke impedance sensor, optical fiber sensor configured tosense stroke and/or respiration among other sensor types. Signalsproduced by the one or more sensors 530 may be communicated to a pacingtherapy controller 510 which includes circuitry 501 for modulating thepacing timing intervals.

Additionally, the therapy controller 510 and the therapy circuitry 535may include functionality to modulate myocardial contractility. Changesin stroke volume can be produced by changes in ventricularcontractility. Patients suffering from heart failure experiencedecreased cardiac contractility that causes a reduction in stroke volumeas well as an increase in preload. The increased preload may lead topulmonary congestion and edema. Non-excitory electrical stimulation maybe used to increase contractility during periods of increased preload.Stimulation to increase contractility may be combined with increased A-Vpaced intervals in situations with increased afterload.

The therapy controller 510 is coupled to the sensors 530, memory 520,cardiac signal sensing circuitry 540, and therapy circuitry 535. Thememory 520 is configured to store program instructions and/or data. Inaddition, the stored information may be used to provide a log of eventsfor display or analysis at a later time. The memory 520 may beconfigured to store program instructions that execute algorithms toimplement modulation of pacing timing intervals. Pacing timing intervalmodulation circuitry 501 executes the program instructions to implementtiming interval modulation in accordance with some embodiments.

The therapy controller 510 is preferably coupled to communicationscircuitry 515 which allows the device to communicate with patientexternal devices 505, such as a patient-external programmer or advancedpatient management system. In some implementations, an advanced patientmanagement (APM) system may be used to collect patient data for purposesof developing patient population data from which coefficients of thetiming interval modulation algorithm may be determined. This data may beacquired from numerous patients. Methods, structures, and/or techniquesdescribed herein, may incorporate various APM related methodologies,including features described in one or more of the following references:U.S. Pat. Nos. 6,221,011; 6,270,457; 6,277,072; 6,280,380; 6,312,378;6,336,903; 6,358,203; 6,368,284; 6,398,728; and 6,440,066, which arehereby incorporated herein by reference.

FIG. 6 shows an embodiment implemented with use of an implanted cardiactherapy device 600. The therapy device 600 includes cardiac rhythmmanagement circuitry enclosed within an implantable housing 601. The CRMcircuitry is electrically coupled to an intracardiac lead system 610.Portions of the intracardiac lead system 610 are shown inserted into thepatient's heart. The lead system 610 includes cardiac pace/senseelectrodes 651-656 positioned in, on, or about one or more heartchambers for sensing electrical signals from the patient's heart and/ordelivering pacing pulses to the heart. The intracardiac sense/paceelectrodes 651-656 may be used to sense and/or pace one or more chambersof the heart, including the left ventricle, the right ventricle, theleft atrium and/or the right atrium. The lead system 610 may include oneor more defibrillation electrodes 641, 642 for deliveringdefibrillation/cardioversion shocks to the heart.

Portions of the housing 601 of the implantable device 600 may optionallyserve as one or multiple can or indifferent electrodes. The housing 601is illustrated as incorporating a header 689 that may be configured tofacilitate removable attachment between one or more leads and thehousing 601. The housing 601 of the therapy device 600 may include oneor more can electrodes 681 b. The header 689 of the therapy device 600may include one or more indifferent electrodes 681 a.

The housing 601 and/or header 689 may include one or more sensors 682,such as an accelerometer or microphone. One or more cardiac leads 610 orseparate sensor leads may incorporate one or more sensors, such as apulmonary arterial pressure sensor. The cardiac electrodes and/or othersensors disposed within or on the housing 601 or lead system 610 of thetherapy device 600 may produce signals used for detection and/ormeasurement of various physiological parameters, such as transthoracicimpedance, respiration rate, minute ventilation, heart rate, cardiacdysynchrony, activity, posture, blood chemistry, 02 saturation, heartsounds, wall stress, wall strain, hypertrophy, inter-electrodeimpedance, electrical delays (PR interval, AV interval, QRS width,etc.), cardiac chamber pressure, cardiac output, temperature,respiration sinus arrhythmia, heart rate variability, depolarizationamplitudes, depolarization timing, and/or other physiologicalparameters. It is contemplated that, in certain embodiments, informationderived from such signals may be incorporated into the algorithm that isemployed to determine modulated pacing timing intervals for pacingtherapy.

In some configurations, the implantable device 600 may incorporate oneor more transthoracic impedance sensors that may be used to acquire thepatient's respiratory waveform, and/or to acquire otherrespiratory-related information. The transthoracic impedance sensor mayinclude, for example, one or more intracardiac electrodes 641, 642,651-656 positioned in one or more chambers of the heart. Theintracardiac electrodes 641, 642, 651-656 may be coupled to impedancedrive/sense circuitry positioned within the housing 601 of the therapydevice 600. Information from the transthoracic impedance sensor may beused to determine an SIR to correspond to the patient's activity ormetabolic need and/or may be used to modulate the pacing rate and/orpacing intervals with respiration cycle phase, among other uses.

Communications circuitry is disposed within the housing 601 forfacilitating communication between the CRM circuitry and apatient-external device, such as an external programmer or advancedpatient management (APM) system. The communications circuitry may alsofacilitate unidirectional or bidirectional communication with one ormore implanted, external, cutaneous, or subcutaneous physiologic ornon-physiologic sensors, patient-input devices and/or informationsystems.

In certain embodiments, the therapy device 600 may include circuitry fordetecting and treating cardiac tachyarrhythmia via defibrillationtherapy and/or anti-tachyarrhythmia pacing (ATP). Configurationsproviding defibrillation capability may make use of defibrillation coils641, 642 for delivering high energy shocks to the heart to terminate ormitigate tachyarrhythmia.

In some embodiments, the implantable therapy device 600 may includecircuitry for selection of pacing electrode(s), timing sequence, and/oramplitude or pulse waveform output configurations (collectively referredto as pacing output configuration) to be applied via one or multipleelectrodes within one or multiple heart chambers. The implantabletherapy device 600 may include functionality to deliverer non-excitoryelectrical stimulation via one or more electrodes. In a pacemakerequipped with multiple pacing electrodes respectively disposed atmultiple pacing sites within a heart chamber, the ability to select oneor more electrodes, temporal sequence, and/or pulse waveformcharacteristics for delivery of pacing can be used enhance thecontractile function of the heart chamber.

Multi-site pacemakers are capable of delivering electrical stimulationto multiple sites of the atria and/or ventricles during a cardiac cycle.Certain patients may benefit from activation of parts of a heartchamber, such as a ventricle, at different times in order to distributethe pumping load and/or depolarization sequence to different areas ofthe ventricle. A multi-site pacemaker has the capability of switchingthe output of pacing pulses between selected electrodes or groups ofelectrodes within a heart chamber during different cardiac cycles. Forexample, the pacing pulses may be delivered to the heart chamber atspecified locations and at specified times during the cardiac cycle toenhance the synchrony of the contraction. Amplitude, pulse duration,anodal/cathodal polarity and/or waveshape of the pacing pulses may alsobe altered to enhance pumping function.

Various modifications and additions can be made to the preferredembodiments discussed hereinabove without departing from the scope ofthe disclosure. Accordingly, the scope of the possible embodimentsshould not be limited by the particular embodiments described above, butshould be defined only by the claims set forth below and equivalentsthereof.

1. A method of delivering pacing therapy to a heart, comprising:adjusting, for each cardiac cycle of a plurality of cardiac cycles, oneor both of an atrioventricular (A-V) timing interval and an atrial (A-A)timing interval to oppose beat-to-beat ventricular (V-V) variability soas to maintain relatively constant V-V intervals between ventricularbeats of different cardiac cycles over the plurality of cardiac cycles;and delivering the pacing therapy using the adjusted timing intervals.2. The method of claim 1, further comprising: determining an indicatedpacing rate based on physiological status; and wherein adjusting one orboth of the atrioventricular (A-V) timing interval and the atrial (A-A)timing interval comprises adjusting one or both of the atrioventricular(A-V) timing interval and the atrial (A-A) timing interval of theindicated pacing rate.
 3. The method of claim 2, wherein determining theindicated pacing rate based on the physiological status comprisesdetermining the indicated pacing rate based on one or more of metabolicneed, autonomic tone, and hemodynamic status.
 4. The method of claim 1,further comprising adjusting one or more of an interventricular delayinterval, an intraventricular delay interval, an interatrial delayinterval, and an intraatrial delay interval.
 5. The method of claim 1,wherein adjusting one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval comprises adjusting one orboth of the atrioventricular (A-V) timing interval and the atrial (A-A)timing interval based on respiration cycle phase.
 6. The method of claim1, wherein adjusting one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval comprises providing ratedependent modulation of one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval to produce optimal strokevolume for each beat.
 7. The method of claim 1, wherein adjusting one orboth of the atrioventricular (A-V) timing interval and the atrial (A-A)timing interval comprises adjusting one or both of the atrioventricular(A-V) timing interval and the atrial (A-A) timing interval initiallydetermined by an algorithm to optimize heart failure therapy.
 8. Themethod of claim 1, wherein a degree of adjusting one or both of theatrioventricular (A-V) timing interval and the atrial (A-A) timinginterval is based on one or both of exertion level and heart rate. 9.The method of claim 1, wherein adjusting one or both of theatrioventricular (A-V) timing interval and the atrial (A-A) timinginterval comprises adjusting one or both of the atrioventricular (A-V)timing interval and the atrial (A-A) timing interval based on one ormore of blood pressure, blood flow, baroreflex and chemoreflex.
 10. Themethod of claim 1, wherein adjusting one or both of the atrioventricular(A-V) timing interval and the atrial (A-A) timing interval comprisesadjusting one or both of the atrioventricular (A-V) timing interval andthe atrial (A-A) timing interval based on cardiac contractility.
 11. Themethod of claim 1, wherein adjusting one or both of the atrioventricular(A-V) timing interval and the atrial (A-A) timing interval comprisesdecreasing beat-to-beat V-V variability at heart rates greater thanabout 140 bpm.
 12. The method of claim 1, further comprising: sensing aphysiological parameter of a right heart chamber during a cardiac cycle;and adjusting one or both of the atrioventricular (A-V) timing intervaland the atrial (A-A) timing interval for a next cardiac cycle based onthe sensed right heart chamber parameter.
 13. The method of claim 1,wherein adjusting one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval comprises adjusting theatrioventricular interval and an interventricular delay interval toprovide cardiac resynchronization therapy.
 14. The method of claim 1,further comprising controlling delivery of non-excitory electricalstimulation to alter myocardial contractility.
 15. The method of claim1, wherein adjusting one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval comprises adjusting theA-A and A-V timing intervals to cancel fluctuations in the V-V intervalswithin one beat at elevated heart rates.
 16. A method of deliveringpacing therapy to a heart, comprising: sensing one or more physiologicalparameters; adjusting, for each cardiac cycle of a plurality of cardiaccycles, one or both of an atrioventricular (A-V) timing interval and anatrial (A-A) timing interval to oppose beat-to-beat ventricular (V-V)variability so as to maintain relatively constant V-V intervals betweenventricular beats of different cardiac cycles over the plurality ofcardiac cycles, the adjusting based on the sensed physiologicalparameters; and delivering the pacing therapy using the adjusted timingintervals.
 17. The method of claim 16, wherein sensing the one or morephysiological parameters comprises sensing one or more right heartparameters.
 18. The method of claim 16, wherein sensing the one or moreparameters comprises sensing one or more of stroke volume, cardiacoutput, total peripheral resistance, pulmonary artery (PA) pressure,hemodynamics, blood flow, blood pressure (e.g., RV, LV, or arterialblood pressure), autonomic tone, baroreflex, chemoreflex, and cardiaccontractility.
 19. The method of claim 16, wherein: sensing the one ormore parameters comprises sensing a right heart chamber parameter duringa first cardiac cycle; and adjusting one or both of the atrioventricular(A-V) timing interval and the atrial (A-A) timing interval comprisesadjusting, during a second cardiac cycle that immediately follows thefirst cardiac cycle, one or both of the atrioventricular (A-V) timinginterval and the atrial (A-A) timing interval based on the one or moreparameters sensed during the first cardiac cycle.
 20. The method ofclaim 16, further comprising: determining an indicated pacing rate basedon physiological status; and wherein adjusting one or both of theatrioventricular (A-V) timing interval and the atrial (A-A) timinginterval comprises adjusting one or both of the atrioventricular (A-V)timing interval and the atrial (A-A) timing interval of the indicatedpacing rate.